Venous thrombosis frequently occurs after major abdominal surgery or leg joint arthroplasty. Currently, therapy is mainly preventive, using low-molecular-weight heparin and warfarin. However, treatment with low-molecular-weight heparin requires subcutaneous administration every day. Warfarin is given orally, but has an exceedingly high protein-binding rate, and this interactivity limits its combined use with other drugs. In addition, both drugs tend to cause bleeding. Thus, if there is an anti-thrombotic agent that is effective over a longer duration, and that does not produce hemorrhagic tendencies, its administration immediately after operation and just prior to discharge from the hospital can prevent thrombosis and improve quality of life (QOL) for patients. The development of anti-thrombotic agents, particularly those effective over longer durations, is also anticipated for other types of thromboses.
A thrombus is formed by the activation of platelets and the blood coagulation system. It is believed that platelets chiefly contribute to the formation of arterial thrombus, while the coagulation system mainly contributes to the formation of venous thrombus. Activation of the blood coagulation system brings about thrombin formation, which leads to the production of fibrin, a major factor in the thrombus network. Meanwhile, thrombin alters its own properties upon binding to thrombomodulin on the surface of vascular endothelia, thus activating protein C (PC). The activated PC (aPC) uses protein S as a coenzyme to inactivate Factors Va and VIIIa, thereby suppressing the coagulation system. Furthermore, aPC comprises the activity of suppressing fibrinolysis-inhibiting substances, such as PAI-1 (Plasminogen Activator Inhibitor-1) and TAFI (Thrombin Activatable Fibrinolysis Inhibitor), and thus enhances the fibrinolysis system. PC and aPC are thus presumed to play important roles in a negative feedback mechanism for the activated blood coagulation system. Indeed, both congenital PC deficiency and aPC resistance due to Factor Va mutations can be causative factors in thrombosis, and thus aPC is expected to be effective in treating and preventing thrombosis.
Although there was no effective drug to treat sepsis, a recent study reported that recombinant aPC was effective in treating sepsis (N. Engl. J. Med. 2001, 344: 699-709). aPC has also been suggested to act on vascular endothelia and to comprise anti-inflammatory activity (J. Biol. Chem. 2001, 276: 11199-11203). In addition, the anti-inflammatory action in a sepsis model is reported to be based on an activity other than the suppression of thrombin production (J. Clin. Invest. 1987, 79: 918-25).
The half-life of aPC in blood is very short (only 20 to 30 minutes), requiring its continuous intravenous administration or long-term repetitive administration. The reason for this short half-life is that aPC is irreversibly inactivated by physiological inhibitors in the body, such as protein C inhibitor (PCI) or α1-antitrypsin (AAT). Even if PC, the precursor of aPC, is used in preparations, its half-life in vivo is as short as six to eight hours. Therefore, such preparations should be administered continuously or frequently, which is inefficient from the viewpoint of healthcare economics.